ROGERADAMS,SCOTT MACKENZIE, JR.,
6 64
able in many respects to the Wolff-Kishner procedure.
Experimental All compounds prepared are described in Tables IIVII. 3 ,S-Dimethoxyphenyl Alkyl Ketones.-These ketones were prepared in the usual way12 in ethyl ether without the addition of dibutyl ether. 3,s-Dimethoxyphenyl Olefins.-The olefins were prepared by the procedure of Adams, Chen and Loewe.' 3,s-Dimethoxyphenyl Alkanes.-The two 1'-methylalkyl derivatives were obtained by catalytic reduction of the ketones a t high temperature and pressure in the presence of copper chromite as a catalyst. A typical conversion of a ketone t o the correponding methylene compound is the preparation of RCH,CHKH(CH,) CHXHa, where R = 3,5-dimethoxyphenyl. A mixture of 18.5 g. of RCOCH2CH(CH3)CH2CH8 and 3 g. of copper chromite catalyst was heated at 260" under an initial pressure of hydrogen (before heating was begun) of 3100 pounds. The hydrogen uptake reached the theoretical in seven hours. After cooling the bomb was opened, and the product rinsed out with ethanol, filtered and distilled. The yield of product was 13.5 g. (78%). 5-A&ylresbrcinols.-The cleavage of the ethers was carried out as previously described.
AND
s. LOEWE
Vol. 70
5-methyl-2-carbethoxycyclohexanone was effected according to the method of Adams, Chen and Loewe.' l-Hy&o~3-~yl-6,6,9-~ethyl-7,8,9,lO-tetrahy&oB-dibenzopyrans.-The conversion of the pyrones to pyrans utilized the conventional treatment with 12 moles of methylmagnesium iodide.9
Summary
1. Two new tetrahydrocannabinol homologs with the groups -CH(CH3) (CH&CH3 and -CH(CHB)(CH&CHa in the 3- position have been synthesized. 2. The activity of the 1'-methyloctyl homolog is 32. This is the most potent substance ever tested, having an activity over four times that of natural tetrahydrocannabinol. The 1 '-methylnonyl, presumably because of decreased solubility, has a potency of only 2.08 but the duration of peak effect is five times that of its congeners. 3. Three isomeric methylpentyl groups have also been introduced into the 3- position, namely, -CH2CH(CHa)CH2CH2CH3, -CH2CH&H(CH3)CHaCHaand -CH2CH2CH2CH(CH3)2. 4. The activities of these isomers varies inl-Hydroxy-3-alkyl-9-methyl-7,8,9,10-tetrahydrod-di- versely as the distance of the methyl group from benzoDvrones.-The condensation of the resorcinols with the ring.
__
( 1 2 ) Suter and Weston, THIS JOURNAL, 61, 232 ( 1 9 3 9 ) .
[CONTRIBUTION FROM THE
RECEIVED JUNE 7, 1947
URBANA, ILLINOIS
NOYESCHEMICAL. LABORATORY, UNIVERSITY
OF ILLINOIS, AND THE SCHOOL OF
MEDICINE
UNIVERSITY OF UTAH]
Tetrahydrocannabinol Homologs with Doubly Branched Alkyl Groups in the 3-Position. XVIII' BY ROGERADAMS,SCOTT MACKENZIE, JR., In synthetic tetrahydrocannabinols with nalkyl groups or alkyl groups with a methyl substituent next to the ring in the 3-position the marihuana potency reaches a maximum of peak activity as the chain is lengthened. The significant increase in activity resulting from the introduction of a methyl group in the 1'-position of the 3-alkyl group stimulated a study of the activity of homologs having more highly branched side-chains in the 3-position. Five pyrans have now been prepared, two of which, (I) and (11), have two methyl groups on the 1'-carbon of the side-chains in the 3-position. The other three, (111))(IV) and (V), have two alkyl groups, one on the 1'-carbon and the other on the 2'-carbon of the side-chain.
____ ( 1 ) For previous pnper see Adams. Aycock and Loewe, THIS JOURNAL, 70, 662 (1948).
AND
S.LOEWE
CHn CH3
All products were tested by a procedure described previously. Activities of these compounds and certain isomers are listed for comparison in Table I. Examination of Table I reveals the extreme variation in potency induced by changes in the structure of the 3-alkyl substituent. Branching of the side-chains not only increases activity but also requires larger groups to attain the maximum of peak effect (compare nos. 3 and 8). It is not surprising that the compound having the l',l'dimethylbutyl side-chain in the 3-position is the most potent of the hexyl series of compounds. The substances with the l',l-dimethylalkyl substitution have activities comparable to the corresponding monomethyl derivatives, and the activity is much higher in the compound with a straight chain of seven carbon atoms than with
Feb., 1948
TETRAHYDROCANNABINOL HonroLocs WITH DOUBLY BRANCHED 3-ALKYL GROUPS 665
PHARMACOLOGICAL
TABLE I ACTIVITYOF TETRAHYDROCANNABINOL
CHa?
CHJ
HOMOLOGS 3-Substituent
1 2
No. of expts.
-Cb”I1-nZ 20 Natural tetrahydrocanna. binol from cn~inabidiol~ 20
Potency
1.00 Standard
7.3
* 0.89
Hexyl Isomer.:
3 -C,,H,4-?LZ 4 5 0 7
-CH(CHa)CdHp’ -CII(CzHb)CH( CHa) CHs -CH(CHs)CH(CHa)CzHs -C(CHJ)ZC~HI
* 0.18 (mas.
7
1.82
8
in n-series) 3.17 * 0 . 3 3
C,
4
5
3.40 3.80 4.18
* f
1.10 0.32
f
0.34
8
-CH(CH,)C,Hu’
9 -CH (CHa)CH(CHa)CaHii 10 -C(CHa)zCc“a
19 32.6
*
CH,
x
Nonyl Isomers
3.02 (inas.
in s-series) 18 512 f 72.6 5 21.8 * 1.91
OH
I
I
“co -o/
CHJ
one of four carbon atoms. Although the 1’,2’XI1 dimethylalkyl derivative with a total of six carbon atoms present in the side-chain is about equal in The nitrile (VII) was converted by the action of potency to the 1’,1’-dimethylalkyl derivative, the ethylmagnesium bromide to the corresponding keisomeric 1’,2’-diniethylalkyl analog with seven tone which with hydrogen and copper chromite carbon atoms in the straight chain exceeds in ac- catalyst was reduced to the carbinol (VIII). tivity the corresponding 1’,1‘-isomer, and indeed Attempted dehydration of VI11 by acidic rehas a value of 512. This is about sixteen times as agents always resulted in rearrangement ; the potent as the most active homolog previously syn- olefins thus formed were isolated, reduced and conthesized and seventy times the potency of na.tua1 densed to the pyrones, the structures of which tetrahydrocannabinol. The new order of the were demonstrated by synthesis using unequivocal marihuana activity of the compound having the methods. The xanthate method of dehydration 1’,2’-dimethylheptyl side-chain makes generaliza- described by Tschugaeff’ produced the unrearranged olefin (IX). This was reduced, demethyltion difficult a t this time. The 1’,1’-dimethylalkylpyrans were synthesized ated, converted to the pyrone (XII), then to the from 3,5-dimethoxybenzaldehyde. The alde- pyran by the procedure previously described.4,8 Although Tschugaeff’s assertion that no rehyde, first prepared by Mauthner6 by the Rosenitiund reduction, was obtained from the acid by arrangement occurs when-alcoholsare dehydrated the method described by McFadyen and Stevensa by the xanthate method was further substantiated , ~ structure of the tertiary olefin through 3,3-dimethoxybenzoyl-p-toluenesulfonyl-by W h i t m ~ r ethe hydrazide. The aldehyde was hydrogenated in was more conclusively established. Dehydration the presence of platinum oxide catalyst and the of the pentanol (VIII) with acidic reagents would resulting benzyl alcohol was converted through lead to the formation of either of two rearrangethe corresponding chloride and nitrile (VI) to ment products, (XIII) or (XIV). Both of these 2 - (3,s- dimethoxyphenyl) - 2 - methylpropionitrile (VTT). CHZO e-(!?=,CH2CH3 0\ l-C=CCH, i CHa
,
I
CHiO
I CHsO
CHB
VI VI I Both pyrans with two carbons on the l‘-carboii atom in the side-chains were prepared from this nitrile (VII) by the scheme shown below for the hexyl compound (VII-XII). (2) Adams. Loewe, Jelinek and Wolff, THIS JOURNAL,63, 1971 (1941). (3) Adnms, Prase. Cain and Clark, ibid., 64, 094 (1942). (4) Adams, Chen and Loewe, ibid., 67, 1534 (1945). (5) Mauthner, J . grakl. Chem., 100, 176 (1020). (6) McFadyen and Stevens, J . Chem. Soc., 584 (1936).
olefins were synthesized from 3,5-dimethoxybenzamide’O by conversion first to the ketone with the appropriate Grignard reagent, followed by the action of methyl- or ethyl-magnesium halide to form the carbinol. These were dehydrated, reduced and demethylated to the resorcinols which were converted to the pyrones. (7) Tschugaeff, Bcr., 34,3332 (1889). (8) Adams and Baker, THIS JOURNAL, 62, 2408 (1040). (9) Whitmore and Simpson, ;bid,, 66, 3809 (1933). (10) Suter and Weston, ;bid,, 61, 232 (1939).
ROGERADAMS,SCOTTMACKENZIE, JR.,
666
AND
S. LOEWE
VOl.
'io
110"). The yield of fine lusterless needles, m. p. $5-46", was 8 g. (68%). Mauthnersreported m.p. 45-46 RCONHz +RCOCHR' --+ 3,s-Dimethoxybenzyl Alcohol.-The aldehyde was hydrogenated a t room temperature and a t 2-3 atm. pressure OH in the presence of platinum oxide catalyst. Ethanol was used as the solvent. The yield of fine white needles, R" R" m. p. 47-48", from 16.6 g. of aldehyde was 16.0 g. (95%). I The reported m. p. is 47-48°.5 R-&=CR' +R-cHCHRp 3,s-Dimethoxybenzyl Chloride.-A solution of 22.5 g. 1 I of purified thionyl chloride in 100 ml. of anhydrous ether CHa CH3 was added in 20-1111. portions with occasional shaking t o a R = 3,5-dimethoxyphenyl; R' = C2H5,R" = CH3; R' = solution of 15 g. of 3,5-dimethoxybenzyl alcohol and 1 ml. CH3, R" = CzHj of pyridine in 200 ml. of anhydrous ether. The mixture was allowed to stand for fifteen minutes and then was exNeither of the pyrones was identical with the tracted twice with 100-ml. portions of cold water. The pyrone (XII) prepared from the neopentyl type ether was allowed to evaporate in W G U O at low temperacarbinol by the Tschugaeff method. The tertiary ture. The crude chloride was purified by recrystallizastructure of the olefin (IX) obtained by the xan- tion from petroleum ether (b. p. 90-110"). The yield of thate method is thus confirmed. The pyrones fine needles, m. p. 46", was 16.0 g. (96%). Anal. Calcd. for CSH1102Cl: C, 57.91; H, 5.90. were converted to pyrans in the usual way. Found: C, 57.94; H, 6.09. 3,s-Dimethoxybenzyl Cyanide.-A mixture of 16 g. of Experimental 3,54imethoxybenzyl chloride, 300 ml. of ethanol, 30 g. of The procedures used for the conversion of a 5-alkylresor- sodium cyanide and 75 ml. of water was refluxed for three cinol dimethyl ether to the corresponding pyran have been hours. The solution was poured onto 400 g. of ice. The described previously.8 solid was collected on a filter and purified by recrystallizaEthyl 3,s-Dimethoxybenzoate.--A mixture of 100 g. of tion from petroleum ether (b. p. 90-110'). The yield of 3,5-dimethoxybenzoic acid, 350 ml. of anhydrous benzene, fine lusterless needles, m. p. 53 ', was 14.5 g. (95%). 2 ml. of pyridine and 300 g. of purified thionyl chloride Anal. Calcd. for CIOHIINOZ:C, 67.80; H, 6.21. was refluxed for three hours. -After removal of the solvent Found: C, 67.81; H, 6.42. and excess thionyl chloride by distillation, 300 ml. of cold 2- (3,s -Dimethoxyphenyl) -2-methylpropionitrile .-3,5absolute ethanol was added to the cooled residue. The re- Dimethoxybenzyl cyanide was methylated using a slight sulting solution was refluxed for four hours. The ethanol was removed by distillation and an ethereal solution of the modification of the procedure described by Smith and Spillaneil for the preparation of 2-(3,5-dimethylphenyl) residue was extracted with aqueous sodium bicarbonate. After removal of the ether the residue was distilled under 2-methylpropionitrile. The sodaniide solution obtained reduced pressure. The product, collected at 120-125" (3 from 3.5 g. of sodium, 200 ml. of liquid nmmonia and a mm.), was a colorless liquid, G ~ 1.5214. ~ D The yield was few crystals of ferric nitrate was allowed to evrrporate to L volume of about 75 ml. The remaining ammonia was 100 g. (879;). displaced by 200 ml. of anhydrous ether and a solution of Anal. Calcd. for C I I H , ~ O ~ :C, 82.86; H , 6.67. 25 g. of 3,5-dimethoxybenzyl cyanide in 100 ml. of anhyFound: C, 63.05; H, 6.79. drous ether was added all a t once and the mixture refluxed 3,5-Dimethoxybenzhydrazide.-A mixture of 100 g. for eighteen hours. Then 25 g. of methyl iodide was added of ethyl 3,54imethoxybenzoate, 100 g. of 85% hydrazine to the cooled solution as rapidly as possible with stirring. hydrate and 110 ml. of absolute ethanol was refluxed for The solution was refluxed for two hours, heating was diseight hours. The yield of brilliant white plates obtained continued and 50 ml. of ethanol was added with stirring. by cooling the solution was 97 g. (83.5?40). The product After washing and drying the reaction mixture was again was purified from ethanol, m. p. 168-169" (cor.) subjected to methylation. \Vhen reaction was complete the solveiit was removed Anal. Calcd. for C P H I ~ N ? ~C,~ :55.10; H, 6.12. nud the crude product obtained by distillation tinder reFuund: C, 55.17; H, 6.15. 3,5-Dimethoxybenzoyl-p-toluenesulfonylhydrazide.-A duced pressure was heated for one hour with 0.25 tablemixture of 100 g . of 3,5-dimethoxybenzhydrazide, 100 spoonful of Raney nickel and 200 ml. of absolute ethanol g. of p-toluenesulfoiiyl chloride and 100 ml. of pyridine to remove any amide. Upon fractionation, a yield of was heated for one hour on a steam cone and then allowed 21.5 g. (72.5%) was obtained. The colorless product, to stand overnight. The solution was poured into 750 b. p. 147-150", 12% 1.5201, dm, 1.0813, became slightly ml. of water and stirred until a granular, light brown solid yellow on standing. Anal. Calcd. for C1211,s?;0,: C, 70.24, H, 7 . 3 2 . was produced. The product was purified by recrystallization from aqueous ethanol. The total yield of large Found: c , 70.03; H,7.53. brilliant plates, m. p. 165-166", was 117.5 g. (7970). 2-(3,5-Dimethoxyphenyl)-2-methylpropanoic Acid: - A Anal. Calcd. for C16H18N2O5S: C, 54.80; H, 5.14. iriixture of 50 ml. of ethylene glycol, 1 g. of the I J ~ O liionitrile, 1 g. of potassium hydroxide and I nil. of water Found: C, 54.90; 13, 5.34. 3,5-Dimethoxybenzaldehyde.-Into a one-liter Erlen- was refluxed for four hours. The solution was diluted with water, extracted with ether, acidified and extracted four meyer flask heated by an oil-bath were placed 100 ml. of glycerol and 25 g. of 3,5-dimethoxybenzoyl-p-toluenesul- times with ether. After removal of the solvent the crudc p. 90fonylhydrazid:. The mixture was stirred manually and acid was recrystallized from petroleum ether l I O C ) . The yicltl of colorlcss cry.;t.,ls, m . 1 1 . Il!l , \vas 0.5 heated to 125 . A hot (IOU") soltition of 20 g. of potassium carbonate in 100 ml. of glycerol was :idded all a t g. Mi(,;). : I u d . Calcd. for C , ~ l i , 6 0 a :C , (i4.29; I f , 7.14. once. The solution was heated rapidly to 135-140' aud maintained a t this temperature for about thirty seconds. Found : C, 64.45; H, 7.20. After the evolution of gases partially subsided the solution 2 -Methyl-Z -(3,5-dimethoxyphenyl) -3-pentanone .-A was poured onto 300 g. of ice. The aqueous suspension solution of 26 g. of 2-methyl-2-(3,5-dimethoxyphenyl)was extracted three times with ether and the ether portions propionitrile in 100 ml. of ;inhydrous ether was added to were combined arid dried over anhydrous magnesium sul- the Grigrixd reagent prcparc*tl from 41.2 g. uf ethyl t r o fate. After removal of the ether the liquid residue was mide, 5.9 g. of maguesiuln and 200 ml. of dry ether. The distilled under reduced pressure. The fraction collected ether was replaced by 300 ml. of dry benzene and the soluat 125-130' (1-2 mm.) was crude aldehyde and was puri(11) S m i t h and Spillane. THISJ O U R N A L , 66, 202 (1043). fied by recrystallization from petroleum ether (b. p. 90CHI
I
R" CHs
.
I I +R-C-CHR' I
(F.
Feb., 1948
TETRAHYDROCANNABINOL HOMOLOGS WITH DOUBLY BRANCHED %ALKYL GROUPS 667 TABLE I1
R
-
KETONES Analyses,
c
3,5-Dimethoxyphenyl
Yield,
%
OC.
B. P . ,
n%
Mm.
Empirical formula
dm4
RC(CHP)ZCOCZHL 70 104 0.3 1.5165 1,0476 RCOCH(CHa)CzH? 76 124-128 0.5 1.5266 .... RCOCH(CH3)CH3a 71 117-119 1.0 1.5290 1.0928 RC(CH&COCF,HII 78 110-145 0.5 1.5088 1.0131 RCOCH(CH;!)C6H1in 82 147 1.0 1.5136 . .. . a Ketones prepared from 3,5-ditnethoxybenzamide contained traces of tion. Refluxing an alcoholic solution with Raney nickel was helpful.
Calcd.
TABLE I11 3,5-DIME:THOXYPHENYL OLIsFINS 7 -
R = 3,B-Dimethoxyphenyl
Yield
B. p.
OC.
Mm.
Empirical formula
d2%
n%
C
Calcd.
RC (CHJ)~CH=CHCH3 75 103-106 0 . 5 1.5179 0.9858 C14Hm0z 76.32 RC(CH,)=C( CHI)CzHa 91 110 1 . 0 1.5277 1,0126 C i ~ H ~ O 76.32 ~ RC(CzHs)=C( CH3) CH? 75 102-106 0.5 .. . . . . C~dHloOz 76.32 RC(CH3)2CH=CHCdHp 90 127-130 0 . 5 1.5080 0.9862 Cl7HzeOz 77.86 RC(CH3l=C(CHp)CsHii 85 132-134 1 . 0 1.5131 0,9616 C17H2601 77.86 * The sample of this compound, made to check the identity of the corresponding pyrone, was purification. TABLE 1V 3,5-DIMETHOXYPHENYLALKANES
..
Yield,
B. I).
yo 'C. Mm. ?:>OD 92 115-117 1.5-2 1.5071 R-C(CHa)zCaH," R-CH(CH3) CH (CHa)CzHsh 91 98-100 0 . 5 1.5012 R-CH ( c ~ H ~C)H ( C H ~C) H ~ ~ , ' ~ 73 104 .5 .... 93 122 .5 1.5006 R-C (CH&CeH1aC 79 120 .5 1.5036 R-CH(CH,)CH(CH~)C~~HI," re using :Raney nickel. 0 Olefin hydrogenated a t roo a t 175' using copper chromite. R = 3,5-Dimethoxyphenyl
d%
R-C(CHdGH7 R-CH(CHI)CH(CH~)C~H~ R-CH(C.H,)CH(C~I,)CH," R-C(CH~)ZCRHI:< R-CH(C€l:,)CH(C~I,)C,Hii
Yield,
II. p.
%
OC.
75 84 50
151-154 145-146 145 161-163 167-169
80
80
Mm.
Empirical formula
1.0 1.0 0.5 0.5 3 0
C12H1s02 CizHisOz CizHisOz Cl,HlsOi Cl,H,sOj
tion was refluxed for forty-eight hours. The reaction mixture was decomposed with dilute sulfuric acid and the benzene was removed by distillation. The resulting mixture of acid and crude ketone was heated for an additional two hours on the steam cone. After cooling the mixture was extracted with ether, and the ether was removed. The crude product was distilled twice under reduced pressure to give a yield of 21 g. (70%) of colorless liquid (Table 111). 2 -Methyl -2 - (3,s-dimethoxyphenyl) -3 -pentan01.--The ketone was hydrogenated a t a temperature of 150170" under a pressure of hydrogen of 3000 pounds in the presetice of copper cliroiiiitc. The product was fractionated under reduced pressure, those fractions having 7 t z 0 ~ 1.5249 * 0.0001 being combined. The yield of colixless, viscous liquid, b. p . 129-130'(0.5 mm.), dad 1.0980, was 15.2 g. (72.570;). Anal. Calcd. for CllH&: C, 70.59; IT, 9.24. Found : C, 70.52; 11, 9.44. 2 -Methyl-2- (3,s-dimethoxyphenyl) -3-pentene.---A solution of 15.2 g. of the pentanol in 100 ml. of dry ether was allowed to react over a six-hour period with a suspension of 2.5 g. of nict:illic potassium (previously
Found
Analyses, 70--
H
C
H
9.15 76.43 9.34 9.15 76.46 9.27 9.15 ... 9.92 77.90 10.10 9.92 77.83 9.94 too small for adequate
...
%-
-Analyses,
Empirical formula
Found
c Calcd. H
Found
C
H
0.9834 CiaHZzOz 75.68 9.91 75.69 10.08 0.9787 CliHp202 75.68 9.91 75.85 10.01 ... . . . . CirHziOz 75.68 9.91 . . . 0.9558 Ci7H2802 77.27 10.61 77.64 10.80 0.9523 CiTHzaOz 77.27 10.61 77.51 10.73 Olefin subjected to two successive hydrogenations
TABLE V 3,5-DIHY DROXYPHENYL ALKANES R = 3,b-Dihydroxyphenyl
%
C H C H CirHaOa 71.19 8.47 71.02 8.45 C13HisOa 70.27 8.11 70.03 8.18 ClzHie03 69.23 7.09 69.28 7.82 C I ~ H Z ~ O73.38 ~ 9.35 73.33 9.51 CieHu03 72.72 10.00 72.58 9.31 the amide which were not removed on redistilla-
,-C
Calcd.
74.19 74.19 74.19 70.27 76.27
Analyses, % '
Found
H
C
9.34 9.34 9.34 10.17 10 17
74.37 74.03
9.29 9.34
70.12 7ti 27
10.12 10 12
...
H
..,
powdered in Stanolind) in 200 ml. of ether. An equimolar quantity of carbon disulfide was added and the mixture was stirred for onefhalf hour. To the thick white mass was added 9.0 g. of methyl iodide. The suspension was refluxed for six hours and allowed to stand overnight. The potassium iodide was removed by filtration. After removal of the ether the yellow residue was placed in a 50ml. modified Claisen flask and distilled under reduced pressure. About one-half hour of careful heatiug was necessary before the actual distillation of light yellow product began. An alcoholic solution of the distillate was refluxed with Rnney nickel and redistilled. The final product was it colorle4s liquid (Table I1 I ) . 2-Methyl-2 -(3,5-dimethoxyphenyl) -3-octanone .-A solution of 18.6 g. of 2-methyl-2-(3,5-dimethoxyphenyl) propionitrile in 100 ml. of anhydrous ether was added to the Grignard reagent prepared from 42.1 g. of n-amyl bromide, 6.63 g. of magnesium and 150 ml. of anhydrous ether. After replacement of the ether with dry benzene the mixture was refluxed for forty-eight hours. The decomposition with dilute sulfuric acid and the purification of the product were carried out as described for the pentanone (Table 11).
ROGERADAMS,SCOTTMACKENZIE, JR.,
668
AND
Vol. 70
S. LOWE
TABLEVI 1-HYDROXY-3-ALKYL-g-METHYL-7,8,9,10-TETRAHYDRO-6-DIBENZOPYRONES M. p. r Analyses, % Yield.’ ($or.) Solvent for Empirical Calcd. Found % C. recryst. formula C H C H
3-Substituent
-C(CHI)ZCIH? -CH(CHa)CH(CHa) CsH6 -CH(CiH6)CH(CHj)CHn
-CH (CH3)CH(CH,)CsHit
73 30 28 36.5 24
218-220 177-178 181-182 156-157 134-136
Ethanol-water Ethanol-water Ethanol-water (1) Nitromethane
>
CmHisOa 76.50 8.28 76.33 CaHztjOj 76.50 8.28 76.63 CmHnaOs 76.50 8.28 76.47
C P ~ H Z O X77.53 8.99 (2) Ethanol-water (1) Nitromethane ‘\ C L ~ H ~ 77.93 ~ O ~ S 9!1 (2) Ethanol-water /
77.52
8.31 8.30 8.45
9.17
76.73 0.14
The yield depended considerably on sample size. TABLEVI1
---
1-fIYDROXY-3-ALKYL-6,6,g-TRIMETIlYL-7,8,9, 10-TETRAHYDRO-6-DIBENZOPYRANS c
3-Substituent
-C(CHa)zCaH7 -CH(CH~)CH(CHI)C~H~ -CH(CzHs) CH (CH,)CHs’ -c(CH~)zceH13 -CH(CHj)CH(CHs)CJ-I,,
f
Yield,
B. p.
%
OC.
65 72 40 65 80
158 160-162 176 176-176 170-173
Mm.
0.02 .02
Empirical formula
C
Calcd.
Cr~HjiOe 80.43
Analyses, %---- Found
H
9.82 9.82 9.82 10.27 10.27
C
80.18 80.64
n 9.75 9.76
C?&z02 80.48 C ? ~ H J ~ 80.43 O~ ... ... Ci&& 81.08 80.98 10.43 .04 c ~ ~ H 81.08 ~ o ~ 80.81 10.48 The sample of this compound, made primarily to check the identity of the corresponding pyrone, was too small for .1 .04
adequate purification. The pyrone, was purified to constant melting point. 2 -Methyl-2-(3,S-dimethoxyphenyl) -3-octanol .-The ke tone was hydrogenated in the presence of copper chromite under conditions identical with those described above. After fractionation under reduced pressure, the yield of colorless liquid, b. p. 162’ (0.5 mm.), 11% 1.5138,dmd 1.0262, W ~ S15.5 g. (79%). Anal. Calcd. for C17H2803: C, 72.86; H, 10.00. Found: C, 72.72; H, 10.19. 2 -Methyl-2 (3,s-dimethoxyphenyl)-3 -octene .-The prep aration of the xanthate was carried out as described above. Gentle heating for three hours was necessary before the decomposition was complete (Table 111).
converted by previously described methods to the corresponding pyrans. 3. The resorcinols for the last three substances mentioned in (1) were made from 3,ti-dimethoxybenzamide. This was converted as follows to the resorcinol dimethyl ether derivatives : -CONH2 -+ -COCH(CHa)R --+ --C(R’)(OH)CH(CH3)R - + -C (R’)=C (CH.3)R -+ -CH (R’)CH (CHa)R. 4. The substances with *the l’,l-dimethylalkyl substitution have activities comparable to the corresponding monomethyl derivatives, and Summary the activity is much higher in the compound with 1. Tetrahydrocannabinols have been prepared a straight chain of seven carbon atoms than with with the following alkyl groups in the 3-positions: one of four carbon atoms. Although the 1’,2’- C ( C H ~ ) Z C H ~ C H ~ C H ~-C(CHa),CH,(CH,),, dimethylalkyl derivative with a total of six carCH1, -CH (CH.3)CH (CH3)CH2CH3, -CH (CH,) - bon atoms present in the side-chain is about equal CH (CHa)CH2(CHt)&H3, -CH( CzH6) CH(CH3)z. 2. The resorcinols required for the first two in potency to the l‘,l’-dimethylalkyl derivative, were synthesized from 3,5-dimethoxybenzoic acid. the isomeric 1’,2’-dimethylalkyl analog with seven This was converted to the resorcinol dimethyl carbon atoms in the straight chain exceeds in activity the corresponding 1’,1‘-isomer and indeed ether derivatives by the following steps: -COOH, + -CHO -+ -CH20EI -+ -CH2Cl -+ has a value of 512. This is about sixteen times as potent as the most active homolog previously syn--CH&N -+ -C(CH3)2CN + -C(CH3)?COthesized and seventy times the potency of natural -C(CHa)2i CHzK + --C(CH3)ZCHOHCH2R -tetrahydrocannabinol. Finally, deCH==CHR -+ -C(CH&CH2CH2K. ILLINOIS RECEIVED JUNE 7, 1947 methylation yielded the resorcinols which were URBANA,
